Abstract Cardiac arrest (CA) has devastating consequences to survival and, even after successful resuscitation brain injury can be quite severe. The broad goal of our research is to develop translational, therapeutic technologies for mitigating brain injury from global ischemia following CA. One prevailing solution is therapeutic hypothermia (TH). While TH has been shown to improve outcome, it does not promote arousal or reduce neuro- inflammation. We now propose a novel and potentially translational delivery approach to promote arousal by intranasal delivery of ORXA. In addition, we also focus on examining the intrinsic bio-distribution and anti- inflammatory properties of dendrimers in a chronic long-term survival after CA. We propose discovery experiments that, we hope to show, will lead to clinically translatable solutions. This proposal is founded on exciting preliminary results. We have discovered an approach to targeting the orexinergic pathway through the delivery of Orexin-A (ORXA). This idea is supported by our preliminary studies that first showed that intra-cerebral ventricle (ICV) ORXA treatment reduces inflammation, and in addition, rapidly enhances arousal. This idea is further validated by our novel quantitative EEG (qEEG) monitoring technology. We have observed brain injury and poor outcome due to neuro-inflammation post-CA brain injury. In our preliminary studies, we found that uptake of dendrimers, specifically Dendrimer- N-acetyl cysteine (D- NAC), occurs at injured brain regions. We have shown that dendrimers serve as a targeted therapeutic technology for neuro-inflammation by attenuating neuro-inflammation, oxidative stress and excitotoxicity. Further, we extend our work to long term observations and set up gender-specific models. For the proposed investigations, we will utilize extensively researched and validated rodent model of CA and resuscitation, propose both acute and chronic experimentation in male and female subjects and carry out the monitoring of systemic perfusion, electrophysiological (qEEG) monitoring, comprehensive behavioral examination, and histopathological analysis. Our overarching hypothesis is that intranasal ORXA will initiate brain arousal effects and early anti-inflammatory response, while dendrimer nanotherapy, D-NAC, will reduce chronic neuro-inflammation; and together, these therapies will improve long term survival. The specific aims of this project are to: Aim 1: Determine the therapeutic effects of intranasal ORXA treatment on early neurophysiological recovery, cognitive and behavioral outcome following post-CA coma. Aim 2: Determine the window of anti-inflammatory therapeutic effects of intranasal ORXA applied immediately post-resuscitation. Aim 3: Demonstrate that treatment with dendrimer nanotherapy using dendrimer conjugated to N-acetyl-L- cysteine (D-NAC), increases survival, improves neurobehavior and reduces chronic neuro-inflammation, after resuscitation. Aim 4: Achieve early arousal and neuroprotective effect from post-CA neuroinflamation by sequentially using of intranasal ORXA and D-NAC for sustained neuroprotection leading to improved long term neurological outcomes and survival post-CA. There are very limited current therapeutic solutions for improving survival and cognitive outcome after global ischemia resulting from CA. Our dual approaches, intranasal ORXA delivery and dendrimer mediated targeting, serve the unmet needs of promoting arousal, and mitigating post-CA neuro-inflammation for patients. Further, the intranasal delivery approach, once validated, should be amenable to rapid clinical translation. Overall, our research lays the groundwork for future clinical studies directed at improving the patient outcome after resuscitation.